The unique, novel approach of HMGene to obesity treatment is to develop drugs that act directly on adipose tissue. The goal of Phase II will be to further validate HMGI-C, an architectural transcription factor which regulates gene expression in adipogenesis, as a drug target in obesity. In Phase I, it was shown that inactivation of HMGI-C reverses the obesity induced by leptin deficiency. Phase II will extend those studies to show that the same holds true for diet induced obesity which is a more physiological model and more closely parallels the human disease. As HMGI-C is a transcriptional regulator and sits at the apex of a genomic cascade, DNA microarray and RNA differential display technology will be used to identify genes in the HMGI-C genomic pathway which will provide novel drug targets. Finally, as the ultimate goal is to develop a safe, effective therapeutic for the treatment of obesity, both biochemical and cellular based assays will be developed in order to screen for small molecule inhibitors of HMGI-C which may be useful in the treatment of obesity. PROPOSED COMMERCIAL APPLICATIONS: Successful completion of this project would open up new prospects of the discovery of effective, clinically valuable anti-obesity drugs, which would have an enormous commercial potential. It is estimated that the U.S. mark for a prescription anti-obesity drug is approximately $ 1 billion in annual sales. For an over-the-counter drug, potential market is believed to be $10 billion.